A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

Logue, Omar C.; Mahdi, Fakhri; Chapman, Heather; George, Eric M.; Bidwell, Gene L.

doi:10.1161/jaha.117.007216

Cited by 35 publications

(32 citation statements)

References 105 publications

(223 reference statements)

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“…In mice after a bolus IV injection, both in this study and in our previous work [29], ELP–VEGF accumulated at higher levels in the liver than in the kidney. However, in rats (after continuous intraperitoneal infusion [35], IV injection, or subcutaneous injection (unpublished data)) and in pigs after intravenous injection [46], ELP–VEGF accumulated in the kidneys at higher levels than in the liver. Interestingly, the addition of KTP to the ELP–VEGF construct redirected the protein toward the kidneys.…”

Section: Resultsmentioning

confidence: 99%

“…Our lab focused on the development of in vivo soluble (high transition temperature) ELP fusion proteins as novel biologics. In one application, we tested an ELP fusion with vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine [29,35,36]. VEGF is a potent inducer of angiogenesis and a stimulator of endothelial cell function [37], and reduced VEGF availability has been implicated in several disease states, including ischemic renal diseases [38,39] and preeclampsia [40].…”

Section: Introductionmentioning

confidence: 99%

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Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer

2019

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Elastin-like polypeptides (ELP) are versatile protein biopolymers used in drug delivery due to their modular nature, allowing fusion of therapeutics and targeting agents. We previously developed an ELP fusion with vascular endothelial growth factor (VEGF) and demonstrated its therapeutic efficacy in translational swine models of renovascular disease and chronic kidney disease. The goal of the current work was to refine renal targeting and reduce off-target tissue deposition of ELP–VEGF. The ELP–VEGF fusion protein was modified by adding a kidney-targeting peptide (KTP) to the N-terminus. All control proteins (ELP, KTP–ELP, ELP–VEGF, and KTP–ELP–VEGF) were also produced to thoroughly assess the effects of each domain on in vitro cell binding and activity and in vivo pharmacokinetics and biodistribution. KTP–ELP–VEGF was equipotent to ELP–VEGF and free VEGF in vitro in the stimulation of primary glomerular microvascular endothelial cell proliferation, tube formation, and extracellular matrix invasion. The contribution of each region of the KTP–ELP–VEGF protein to the cell binding specificity was assayed in primary human renal endothelial cells, tubular epithelial cells, and podocytes, demonstrating that the VEGF domain induced binding to endothelial cells and the KTP domain increased binding to all renal cell types. The pharmacokinetics and biodistribution of KTP–ELP–VEGF and all control proteins were determined in SKH-1 Elite hairless mice. The addition of KTP to ELP slowed its in vivo clearance and increased its renal deposition. Furthermore, addition of KTP redirected ELP–VEGF, which was found at high levels in the liver, to the kidney. Intrarenal histology showed similar distribution of all proteins, with high levels in blood vessels and tubules. The VEGF-containing proteins also accumulated in punctate foci in the glomeruli. These studies provide a thorough characterization of the effects of a kidney-targeting peptide and an active cytokine on the biodistribution of these novel biologics. Furthermore, they demonstrate that renal specificity of a proven therapeutic can be improved using a targeting peptide.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer

2019

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“…We generated a library of ELP constructs using recursive directional ligation as described by Kuna et al [37].…”

Section: Methodsmentioning

confidence: 99%

“…The MW has strong effects on the polymer’s hydrodynamic radius, pharmacokinetics, and biodistribution. We measured the physical and biological properties of these molecules, including their hydrodynamic radius, in vitro stability, pharmacokinetics and biodistribution [37]. The smallest ELP tested included 63 VPGxG repeats.…”

Section: Introductionmentioning

confidence: 99%

Polymer size affects biodistribution and placental accumulation of the drug delivery biopolymer elastin-like polypeptide in a rodent pregnancy model

et al. 2018

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Introduction. Fusion of therapeutic agents to Elastin-like Polypeptide (ELP) is a novel drug delivery strategy for prevention of placental drug transfer. Previous studies have used a 60 kDa ELP tag for this purpose. However, placental transfer of ELP may be size dependent. The goal of this study was to measure the effects of ELP polymer size on pharmacokinetics, biodistribution, and placental transfer of ELP. Methods. Three ELPs ranging from 25 to 86 kDa (4.1 to 6.8 nm hydrodynamic radius) were fluorescently labeled and administered by i.v. bolus to pregnant Sprague Dawley rats on gestational day 14. Plasma levels were monitored for 4h, organ levels and placental transfer determined by ex vivo fluorescence imaging, and placental localization determined by confocal microscopy. Results. Increasing ELP size resulted in slower plasma clearance and increased deposition in all major maternal organs, except in the kidneys where an opposite effect was observed. Placental levels increased with an increase in size, while in the pups, little to no ELP was detected. Discussion. Pharmacokinetics and biodistribution of ELPs during pregnancy are size dependent, but all ELPs tested were too large to traverse the placental barrier. These studies verify that ELP fusion is a powerful method of modulating half-life and preventing placental transfer of cargo molecules. The tunable nature of the ELP sequence makes it ideal for drug delivery applications during pregnancy, where it can be used to target drugs to the mother while preventing fetal drug exposure.

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“…Another approach to combine GFs and biomaterials is to directly create fusion proteins consisting of GFs with ECM proteins. For example, a biopolymer based on the ECM protein elastin was fused to VEGF-A (ELP-VEGF) with the objective to treat preeclampsia, a hypertensive syndrome that originates from an improperly vascularized and ischemic placenta (Logue et al, 2017). Here, ELP-VEGF reduced hypertension in a placental ischemia rat model and did not cross the placental barrier, reducing the risk of adverse effects on fetal development.…”

Section: Engineering Gfs To Be Covalently Bound To Biomaterialsmentioning

confidence: 99%

Growth Factor Engineering Strategies for Regenerative Medicine Applications

Xue-ping

Zhao

Lash

et al. 2020

Front. Bioeng. Biotechnol.

191

130

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Growth factors are critical molecules for tissue repair and regeneration. Therefore, recombinant growth factors have raised a lot of hope for regenerative medicine applications. While using growth factors to promote tissue healing has widely shown promising results in pre-clinical settings, their success in the clinic is not a forgone conclusion. Indeed, translation of growth factors is often limited by their short half-life, rapid diffusion from the delivery site, and low cost-effectiveness. Trying to circumvent those limitations by the use of supraphysiological doses has led to serious side-effects in many cases and therefore innovative technologies are required to improve growth factorbased regenerative strategies. In this review, we present protein engineering approaches seeking to improve growth factor delivery and efficacy while reducing doses and side effects. We focus on engineering strategies seeking to improve affinity of growth factors for biomaterials or the endogenous extracellular matrix. Then, we discuss some examples of increasing growth factor stability and bioactivity, and propose new lines of research that the field of growth factor engineering for regenerative medicine may adopt in the future.

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A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

Cited by 35 publications

References 105 publications

Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer

Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer

Polymer size affects biodistribution and placental accumulation of the drug delivery biopolymer elastin-like polypeptide in a rodent pregnancy model

Growth Factor Engineering Strategies for Regenerative Medicine Applications

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